The increasing prevalence of obesity in the U.S. is well documented by a series of surveys conducted by the National Center for Health Statistics. Its 1999-2000 data revealed that a staggering 62.5 % of adult Americans aged = 20 were overweight (BMI >= 25), and 30.5 % were obese (BMI >= 30). Projections suggest that by the year 2025 45% of adult Americans will be frankly obese. The increasing prevalence of obesity has fueled an increase in obesity-associated healthcare costs that reached $100 billion annually (5.7% of our national health expenditure) by 1995, and is surely even greater today. Obesity is associated with markedly increased risks of many comorbidities, of which hypertension, non-insulin-dependent diabetes mellitus (NIDDM), dyslipidemias, and cardiovascular disease are major contributors to 300,000 obesity related deaths annually. Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a serious complication of obesity, and its most severe form, nonalcoholic steatohepatitis (NASH), is now the third most common indication for liver transplantation. Medical therapies for obesity are of very limited success. The best results for long term control of weight and of the various co-morbidities of obesity derive from bariatric surgery. The Mount Sinai School of Medicine has a large and innovative bariatric surgery program, which has focused on the development of minimally invasive (laparoscopic) bariatric methods. In this application, we propose to study the efficacy and safety of a novel, two stage surgical treatment of morbid-and super-obesity (BMI = 60) that combines an initial restrictive operation (sleeve gastrectomy) with a subsequent malabsorptive procedure (biliopancreatic diversion with duodenal switch) performed after the loss of ca. 100 Ib, when the patient is a better operative risk. Preliminary data suggest the approach is both effective and safe, with an appreciable reduction in operative morbidity and mortality compared with conventional, open abdominal surgery in this population. The nature of the protocol allows collaborating scientists to conduct virtually unique studies of changes in adipose tissue fatty acid metabolism, hepatic histology, triglyceride accumulation and fibrogenesis, patterns of adipocyte and hepatocyte gene expression, alterations in levels of circulating hormones that modulate hunger and satiety, and changes in regional brain activity in response to food stimuli, that result from extensive weight loss. In a second protocol, effects of laparoscopic Roux-en-Y gastric bypass on short and long term control of weight and NIDDM in obese patients with initial BMIs = 35 will be compared with results of ADA-recommended optimal medical care. By conducting this as a cooperative study at multiple sites within the Bariatric Surgery Clinical Research Consortium, the results will make a compelling statement about the optimal approach to control of obesity and NIDDM in this population, that represents an ever-increasing subset of adult Americans.